According to the Official Monograph of USP XXI, Nadolol is identified as follows: ##STR3##
Formula C.sub.17 H.sub.27 NO.sub.4 M.W. 309.41; 2,3-Naphthalenediol, 5-[-3(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-, cis, 1-(tert-Butylamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1-naphthyl)ox y]-2-propanol [42200-33-9]. Nadolol contains not less than 98.0 percent and not more than 101.5 percent of C.sub.17 H.sub.27 NO.sub.4, calculated on a dried basis. Nadolol is also made up of 4 cis isomers.
Many processes have been proposed for the manufacture of Nadolol from various intermediates. There are 4 cis isomers of Nadolol and because each cis isomer of Nadolol produced may have a number of impurities associated with it (from the manufacturing process). Also some of the impurities in the starting materials may themselves become involved in the reaction (the starting materials may only be 80%-85% pure and some of the impurities may be unknowns). Thus, the Official Monograph provides the specifications for Nadolol, and assay procedures for determination of its purity. The Monograph does-not include an HPLC method.
A number of proposals have been made for making Nadolol. See Canadian Letters Patent 979,912; 979,926; 1,000,287; 1,041,544; 1,059,147; 1,063,120; and 1,064,965. Hauck has also proposed processes for separation of the four cis isomers from one another. (See Canadian Letters Patent 1,041,544; 1,059,147 and 1,064,965.) However the processes led to very low yields and are therefore not commercially viable.
Canadian Letters Patent 1,132,560 (Ciba-Geigy) discloses a process for inverting the configuration in optically active compounds characterized in that an optically active compound of the formula ##STR4## having a R(+) or S(-) configuration is converted by treating with concentrated phosphoric acid or concentrated sulphuric acid or a chloride or bromide of such acids, into an optically active compound and the resulting compound is hydrolyzed to form a compound with a configuration opposite to that of the starting material used. This process is complex.
It is therefore an object of this invention to provide an improved process for manufacturing 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3 naphthalenediol in good yields.
Canadian Letters Patent 882,705 discloses a process for the preparation of ##STR5##
Applicant is also aware of the following additional publications (a) "A Convenient Procedure for the Cis-hydroxylation of Olefins" by L. Mangoni et al, Tetrahedron Letters No. 45, pp.4485-4486, 1973; and (b) "A Convenient Modification of the Woodward cis-hydroxylation of Olefins" L. Mangoni et al, Gazz. Chim. Ital. 1975, 105,377.
Woodward in U.S. Pat. No. 2,687,435 (1954) and at J. Am. Chem. Soc. 80,209 (1958) with F. V. Brutcher taught the hydroxylation of an olefin with iodine and silver acetate in wet acetic acid to give cis-glycols. The process involves the "trans" addition of iodine and silver acetate to give a "trans" -iodo-acetoxy-derivative. The latter is hydrolyzed to a cis- mono-glycol acetate with acetic acid and water. Alkaline hydrolysis results in the final cis-glycol.
Brutcher and Evans reported in Journal of Organic
(1957) 23, 618, a modification to the process proposed by Woodward and Brutcher. This modification involved the interaction of an olefin with iodine, silver acetate, and wet acetic acid to give cis hydroxy acetate in one operation. Subsequent hydrolysis was purported to yield the free diol.
Bunton and Carr in an article "The hydroxylation of Cyclic Olefins by Iodine and Silver Acetate", J. Chem. Society (1963) 770 reported results as follows:
"Cyclohexenes.- The Woodward procedure, reaction between 1, 2-dimethylcyclohexene and iodine and silver acetate in `wet` acetic acid (1.5% of water), gave after vacuum-distillation of the product and its recrystallization a 1:1 molecular compound of the cis-and the trans-diol. Stereospecific cis-hydroxylation by this method has been reported previously..sup.3 Reaction in `dry` acetic acid gave no 1, 2-diol.
We therefore studied the oxidation of 1methylcyclohexene by the Woodward procedure and obtained the cis-1,2-diol. In agreement with other workers, we also obtained the cis-diol from cyclohexene by the Woodward procedure and the 'trans-diol by using `dry` acetic acid.
Cyclopentenes. - The reaction between cyclopentene and iodine and silver acetaic in `wet` acetic acid is reported to give the cis-diol in a 48% yield. By this method we converted 1-methylcyclopentene into the cis-diol in 20% yield, but obtained no diol from 1,2-dimethylcyclopentene."
Subsequently Hauck in Canadian Letters Patent 1,041,544 attempted to separate the four optical cis isomers of 2,3-cis-1,2,3,4-tetrahydro-S-[2-hydroxy-3-(tert-butylamino) propoxy]-2,3-naphthalenediol in order to determine the best of these isomers. The processes of manufacture (See pages 4, 5 and 6 of the Patent and example 4 at pages 18 and of the patent) employ water. Crystallization of isomer product is from chloroform. In Hauck's laboratory procedure resulting 1-(2,3-epoxypropoxy)-5,8-dihydronaphthalene is isolated and subsequently reacted with t-butylamine in a high pressure reactor. The resulting dl-1-(tert-butylamino)-3-(5,8-dihydronaphthyl)oxyl-2-propanol is then cis hydroxylated with wet acetic acid, silver iodide, and the resulting acetoxy iodide is hydrolysed with base and finally subjected to catalytic hydrogenation to afford crude Nadolol.
Mangoni et al in an article entitled "A convenient Modification of the Woodward cis-Hydroxylation of Olefins" (Gazz. Chem. Ital. 1975, 105, 377) discussed modifications of the Woodward procedure by subtituting for silver acetate. Wet acetic acid is still used; glacial acetic acid was also tried. No exceptional results are produced by the use of the glacial acetic acid. The cis-diol steroid product is produced with both procedures--in a slightly lesser percentage return using glacial acetic acid than a solution of acetic acid and water.
It is therefore another object of this invention to provide improved processes for the manufacture of Nadolol which unexpectedly yielded Nadolol in a minimal number of process steps, in good yields and Nadolol of substantial purity.
Further and other objects of this invention will be realized by those skilled in the art from the following summary of invention and detailed description of an embodiment thereof.